Cardiovascular (CV) events are the most common cause of death in adults with type 2 diabetes. While the benefits and safety of commonly used blood pressure (BP) and cholesterol medications are well established, much less is known about the CV benefits and CV risks of commonly used glucose-control strategies involving treatment with multiple glucose-lowering agents. To address this important clinical and public health concern, this project examines detailed clinical data from 1.3 million adults with treated type 2 diabetes over a 13-year period to quantify the impact of specific combinations of glucose-lowering agents on myocardial infarction, stroke, CV mortality, total mortality, and congestive heart failure (CHF) hospitalizations. We test four comparative effectiveness hypotheses to determine whether major CV events are differentially related to: (a) use of specific two-agent combinations of metformin with sulfonylurea (SU), thiazolidinedione (TZD), DPP-4 inhibitors, or GLP-1 receptor agonists; (b) use of specific two-agent combinations of metformin with SU, TZD, DPP-4 inhibitors, or GLP-1 receptors agonists when basal insulin is added; (c) addition of prandial insulin in subjects already using basal insulin; and (d) treatment with human insulin versus analog insulin. Analysis employs modern comparative effectiveness statistical approaches, including new user designs and marginal structural modeling (MSM) with inverse probability weighting (IPW) and targeted minimal loss-based estimation (TMLE) which, under certain conditions, allow proper adjustment for time-dependent confounders on the causal pathway between early exposures and clinical outcomes, as well as proper adjustment for selection bias due to informative censoring. The study results have the potential to substantially improve CV outcomes in millions of Americans with type 2 diabetes by identifying which commonly used glucose-lowering regimens maximize CV benefits and minimize CV risks.